This program tests molecular imaging variables, how they predict response to therapy, and how they change over the course of different treatments. We propose 5 interactive projects: 1. Proliferation studies to validate how well FLT compares to TdR in patients with a variety of tumors and explores ways to simplify the PET procedure and still distinguish flux from transport. Our hypothesis is that FLT with appropriate data analysis can be as accurate as TdR for reporting tumor proliferation. We will test the hypothesis that FLT PET plus MRI can distinguish between tumor progression and pseudoprogression in patients with GBM that finish initial therapy with external beam RT plus concurrent TMZ. 2. Tumors have variable levels of multi-drug resistance that reduces effectiveness of drug treatments. We will quantify transporter activity of P-glycoprotein as a suspected cause of treatment resistance and failure by analyzing [11C]-verapamil kinetics. We will test the hypothesis that pts who up-regulate their tumor Pgp activity after neoadjuvant chemotherapy will have shorter survival and time to progression. 3. Hypoxia is an important resistance factor that is imaged using [18F]-FMISO. In pts with brain tumors we will test the hypothesis that FMISO images following initial surgery define an appropriate target for focal boost RT that will improve time to tumor progression and survival. In pts with ER-neg metastatic breast cancer, we will compare the extent of hypoxia to response to systemic therapy and progression-free survival. Other experiments will compare FMISO and [64Cu]-ATSM and we will measure temporal changes using an FMISO test-retest protocol and BOLD-MRI to look for short term changes in regional oxygenation of tumors. 4. This project will test the use of 18F-FES PET to choose therapy in pts with a history of ER+ breast cancer who have failed prior regimens and are being considered for salvage endocrine therapy and use FES PET to measure regional ER as a pharmacodynamic response to endocrine therapy and FDG PET to localize active tumor and identify early effects of drug therapy, including HER2 and ER. The project will also image androgen receptor function in prostate cancer to identify heterogeneous AR expression. 5. Preclinical radiopharmaceutical development and research. New methods will be developed to image important aspects of the tumor phenotype. Some are new molecules; some are new applications for old molecules; all to develop promising imaging agents for characterizing the tumor phenotype. These include ligands for HER2 as a factor in treating breast cancer, new agents for imaging of androgen biology, a monoamine oxidase A ligand to select patients for a new clinical trial for prostate adenocarcinoma and studies comparing Cu-ATSM and FMISO for different mechanisms of uptake.